Sunitinib base is having the chemical name N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide is also known as SU11248 and similar pyrrole derivatives are first disclosed in WO01/060814. Its equivalent patent is U.S. Pat. No. 6,573,293.
The aforesaid patent describes a process for the preparation of Sunitinib as shown in Scheme-1 below.

Accordingly,
In the U.S. Pat. No. 6,573,293, the intermediate of formula II (R=t-Bu) is prepared as procedure described in Org. Synthesis. Coll. Vol. 2, p. 202 (Scheme-I(a)) for similar compound (R=Et).

Later it is selectively decarboxylated in the presence of aqueous alcoholic HCl to get half-ester pyrrole derivative of formula-III.
The compound of formula-III is then formylated by a known synthetic methodology using DMF-POCl3 complex to get the formylated ester derivative of formula-IV.
The ester functionality of derivative of formula-IV is selectively hydrolyzed to get a carboxylic acid derivative of formula-V.
The carboxylic acid derivative of formula-V is then selectively converted to amide of formula-VII using 2-(Diethylamino ethylamine of formula-VI in the presence of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide HCl.
The 5-fluoro-2-oxindole derivative of formula-IX is prepared by the selective reduction of carbonyl functionality of the compound of formula-VIII using 55% hydrazine hydrate. Finally the formyl derivative of formula-VII is coupled with 5-Fluoro-2-oxindole of formula-IX by Knoevenagel method using pyrrolidine as a catalyst to get Sunitinib base of formula-I. The product is characterized by 1H NMR and Mass spectral analysis.
Later the same inventors in the year 2003 disclosed a procedure (Scheme-2) similar to the earlier patent (WO01/060814) with some slight modification. In this patent (WO2003035009), the formylated derivative of formula-V is first reacted with 5-Fluoro-2-oxindole of formula-IX under Knoevenagel conditions using piperidine as a catalyst to get the carboxylic acid derivative of formula-X.

In the same year (2003), a different synthetic methodology (Scheme 3) is disclosed in WO2003070725. In this patent, an imidazole-amide derivative of formula-XI is prepared using carboxylic acid derivative of formula-V in presence of CDI. The resulting imidazole-amide derivative of formula-XI is reacted with N,N-Diethylaminoethylamine of formula-VI to get imine-amide derivative of formula-XII and its in-situ condensation with 5-Fluoro-2-oxindole of formula-IX in acetonitrile at 60° C. for 18 hours affords Sunitinib base of formula-I. Later the method of synthesis is published in J. Org. Chem., 2004, 69, 2565-2568.

A modified process for Sunitinib base of formula-I is published in J. Org. Chem., 2003, 68, 6447-6450 as shown in Scheme-4. In this article the target molecule is synthesized by early amidation approach using diketene of formula-XIII as the staring material.

Process disclosed in the first patent (U.S. Pat. No. 6,573,293 and WO01/060814) for the preparation of Sunitinib base of formula-I has the following disadvantages.                (a) The chemical purity of the intermediates and final product is not disclosed.        (b) In this patent, the intermediate of formula II (R=t-Bu) is prepared as described in Scheme-I(a).                    According to the method of synthesis, tert. butyl acetoacetate and sodium nitrite are reacted at 5-7° C. in acetic acid. The resulting oxime derivative of formula-XV (R=t-Bu) is then condensed and cyclized with ethyl acetoacetate using Zn dust as reducing agent and refluxed at 115-120° C. The product is crystallized in 95% alcohol to get the intermediate of formula-II. Using the above method of synthesis for formula-II, the following disadvantages are encountered.            (i) Yields are not reproducible. By following the same experimental conditions, only 30% yield against 57-64% reported yield is obtained. The low yields may be due to elevated temperatures (115-120° C.) during condensation and cyclization.            (ii) A number of impurities are formed during condensation and cyclization at higher temperatures.            (iii) Considerable frothing is observed while heating the reaction to 115-120° C. which is uncontrollable.            (iv) On bigger scale, decantation is not a suitable operation at higher temperatures.            (v) Work-up procedure is not suitable for plant scale operation.            (vi) We observed that, separation of impurities from the intermediate of formula-II is not easy. It requires number of crystallizations to remove the impurities. This would lead to poor recovery of the wanted intermediate of formula-II.                        (c) Yields are not reproducible in making of formula-III. Since we observed that elevated temperatures (67° C.) reduce yield and purity of the intermediate of formula-III.        (d) In making intermediate of formula-IV, V & VII, very toxic and hazardous solvent methylene chloride would increase pollution load.        (e) Filtration of intermediate of formula-IV as stipulated in the patent WO01/060814, below 15° C. is very difficult since the intermediate forms a pasty mass at this temperature.        (f) Expensive reagent like 1-(3-dimethylamino-aminopropyl-3-ethyl carbodimide hydrochloride is used in the synthesis of compound of formula-VII, which is not commercially available reagent and recyclable. Also it poses lot of pollution.                    (i) Very low yields are reported.            (ii) Highly flammable solvents (hexane and diethyl ether) are used in isolation.            (iii) Multiple solvents are used in the synthesis of formula-VII.                        (g) In the synthesis of 5-fluoro-2-oxindole of formula-IX, 55% hydrazine hydrate is used to reduce the carbonyl functionality at 3rd position of 5-fluoro isatin of formula-VIII.                    (i) Yields are not reproducible.            (ii) Lot of frothing is observed during reaction at 110° C. This is due to low concentration (55%) of hydrazine hydrate.                        (h) In the penultimate step, i.e., condensation of 5-fluoro-2-oxindole of formula-IX with aldehyde derivative of formula-VII, no elaborate solvent study is performed.                    (i) Purity of the Sunitinib base of formula-I is not disclosed.                        (i) No experimental details for the synthesis of Sunitinib malate of formula-I(a) is disclosed.        
Process disclosed in the second patent (WO2003035009) for the preparation of Sunitinib base has the following disadvantages.                (a) In making intermediates of formula-IV & V, very toxic and hazardous solvent methylene chloride would increase the pollution loads.        (b) Filtration of intermediate of formula-IV below 15° C. is very difficult, since the nature of the intermediate is pasty.        (c) In making of formula-X, yields are not reproducible during condensation of compound of formula-V with 5-fluoro-2-oxindole of formula-IX in piperidine/ethanol medium.        (d) Several impurities are encountered during synthesis of formula-X.        (e) No experimental details are given for Sunitinib base of formula-I starting from formula-X.        (f) No experimental details for Sunitinib malate of formula-I(a) is disclosed.        
Process disclosed in the third patent (WO2003070725) for the preparation of Sunitinib base has the following disadvantages.                (a) Usage of carbonyl diimidazole in the synthesis of formula-XI would leads to cost escalation of the final product.        (b) No experimental details for the synthesis of Sunitinib malate of formula-I(a) is disclosed        
Process disclosed in the fourth patent (US2006009510) for the preparation of Sunitinib base of formula-I has the following disadvantages.                (a) Highly toxic reagent like diketene is used in the synthesis, which is not commercially available and handling of such a chemical on industrial scale unviable.        (b) Expensive catalyst like 10% Pd/C is used in the synthesis.        (c) Unstable reagent like chloromethylenedimethylammonium chloride is used for formylation.        (d) No experimental details for the synthesis of Sunitinib malate of formula-I(a) is disclosed.        